Antitumor Activity Observed With Iberdomide in Heavily Pretreated Myeloma

Sagar Lonial, MD

Novel agent iberdomide (formerly CC-220) in combination with dexamethasone was safe and demonstrated antitumor activity in patients with relapsed or refractory multiple myeloma who were heavily pretreated, according to findings from a phase Ib/IIa trial.¹

Overall response rate (ORR) was 32.2% among 59 evaluable patients, comprising a very good partial response rate (VGPR) of 3.4% and a partial response (PR) rate of 28.8%. Minimal response (MR) occurred in 16.9% of patients, 35.6% had stable disease (SD), and 15.3% had progressive disease (PD), accordings to findings presented at the 17th International Myeloma Workshop.

Similar efficacy to that of the whole cohort was shown in patients with multiple myeloma refractory to lenalidomide (Revlimid), pomalidomide (Pomalyst), or anti-CD38 monoclonal antibody therapy.

For the 51 evaluable patients with immunomodulatory drug (IMiD)-refractory multiple myeloma, the ORR was 35.3%, with a 2.0% VGPR and a 33.3% PR. The MR rate was 17.7%, the SD rate was 33.3%, and the PD rate was 13.7%. For the 27 evaluable patients whose myeloma was refractory to daratumumab (Darzalex) and pomalidomide, the ORR was 29.6%, comprising a 3.7% VGPR and a 25.9% PR. In this group 14.8% had MR, 37.0% had SD, and 18.5% had PD.

Clinical activity was seen early in the treatment course and across all dose levels, with some patients remaining on treatment at the time of data cut-off.

Iberdomide is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinical studies showed that iberdomide overcomes IMiD resistance and is synergistic with daratumumab, bortezomib (Velcade), and dexamethasone, demonstrating enhanced apoptosis and antibody-dependent cellular cytotoxicity. Iberdomide induces natural killer (NK) cell proliferation and may help rescue NK cell depletion by daratumumab.

The iberdomide MM-001 phase Ib/IIa multicenter, open-label, dose-escalation study (NCT02773030) was conducted to evaluate the maximum-tolerated dose (MTD), recommended phase II dose, safety, and preliminary efficacy of iberdomide in combination with dexamethasone in patients with relapsed/refractory multiple myeloma.²

The study started with 2 cohorts receiving iberdomide monotherapy or in combination with dexamethasone. Additional cohorts are continuing with dose-escalation and iberdomide in combination with dexamethasone and a proteasome inhibitor (PI) or daratumumab.

Sagar Lonial, MD, Emory University, presented the results from cohort B, in which 66 patients have received iberdomide and dexamethasone.

Eligible patients had relapsed/refractory multiple myeloma and must have received ≥2 prior regimens including lenalidomide and/or pomalidomide, and a PI. All patients experienced progression on or within 60 days of their last myeloma therapy. Escalating doses of iberdomide were given on days 1 to 21, in combination with dexamethasone 40 mg (20 mg in patients aged >75 years) on days 1, 8, 15, and 22, of each 28-day cycle. Dose escalation was reviewed by a dose-escalation committee.

The median age was 65 years (range, 33-79), and the median number of prior regimens was 5 (range, 2-12). Prior therapies included autologous stem cell transplantation (78.8%), lenalidomide (100%), pomalidomide (68.2%), PI (100%), and anti-CD38 monoclonal antibody (74.2%). The patients’ multiple myeloma was refractory to lenalidomide (75.8%), pomalidomide (56.1%), IMiD (86.4%), PI (66.7%), and anti-CD38 monoclonal antibody (71.2%), representing a heavily pretreated population.

Iberdomide dose ranged from 0.3 to 1.3 mg, with a median of 3 cycles (range, 1-31) as of the April 15, 2019, data cutoff. Neither the MTD nor the recommended phase II dose have been reached yet. Dose reductions have been required in 19.7% of patients. Twenty of the 66 patients are receiving ongoing treatment.

Iberdomide was generally well tolerated. All-grade adverse events (AEs) included infection (47%), neutropenia (33.3%), anemia (36.4%), fatigue (30.3%), and gastrointestinal toxicities, and were as expected with an IMiD. Grade ≥3 nonhematologic AEs were rare, other than infection. Only 6 patients discontinued due to an AE, which Lonial said, “speaks to the safety of iberdomide.”

Dose-limiting toxicities (DLT) occurred in 1 patient each at 1.2 and 1.3 mg doses (grade 4 sepsis and grade 3 pneumonia, respectively). Lonial said it was not clear if these were drug-related. He noted that larger numbers of patients were treated at each dose level than in the standard 3 + 3 clinical trial design to help aid in determining efficacy and pharmacokinetic parameters.

This study is ongoing, with enrollment continuing in cohorts evaluating iberdomide and dexamethasone with bortezomib (Velcade), carfilzomib (Kyprolis), and daratumumab (Darzalex).

References:

1. Lonial S, Van de Donk N, Popat R, et al. A phase 1b/2a study of the CELMoD iberdomide (CC-220) in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: The 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 198.
2. A study to determine dose and tolerability of CC-220 monotherapy, in combination with dexamethasone, and in combination with dexamethasone and daratumumab or bortezomib in subjects with relapsed and refractory multiple myeloma (MM). NIH US National Library of Medicine. Posted May 16, 2016. Accessed September 15, 2019. https://clinicaltrials.gov/ct2/show/NCT02773030.